Title: Analgesics Targeting TRPA1 for Treatment of Chronic Pain Abstract An effective treatment for chronic pain that is devoid of both addictive potential and abuse liability is a major unmet need in medicine today. These limitations drive the need for novel treatment options based on new molecular mechanisms. Our goal is to identify and develop a novel, first-in-class therapeutic small molecule compound which is a functional antagonist of TRPA1 (Transient Receptor Potential, Subfamily A, member 1) for the treatment of chronic pain. TRPA1-receptor/channels play a highly specific function in sensory nerves that transmit the sensations of pain and hyperalgesia in response to inflammation as well as nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors, targeting TRPA1 is a logical approach to block nociceptive signals at the first stage of neural processing. A TRPA1 antagonist will function as a peripherally acting analgesic and is thus designed to be without addictive and abuse potential. Algomedix employs an innovative rational pharmacology approach which has proven capable of identification of multiple new chemical scaffolds with potency equivalent to established TRPA1 ligands. Algomedix employs a kinetic selectivity profiling approach to characterize drug action which has resulted in identification of new pharmacologic classes for TRPA1. Our approach can identify TRPA1 ligands which are classical antagonists, desensitizing agonists, inverse agonists and allosteric modulators. The aims are: AIM 1 will be to synthesize a group of 30 novel, patentable structural analogs based upon 3 newly discovered TRPA1 ligand active scaffolds. We will initiate medicinal chemistry efforts for enhancing lead potency, selectivity optimization, and to establish structure activity relationship (SAR) analysis. AIM 2 will be to define the potency, pharmacological activity in human and rat TRPA1, kinetics of activation and/or densensitization for novel compounds. AIM 3 will be to define the pharmacological selectivity using a panel of related TRP channels using TRPV1, TRPV3 and TRPM8: AIM 4 wil be to pharmacological Characterize Activity Using Dorsal Root Ganglion (DRG) cells: Kinetics, Homologous TRPA1 Desensitization and Cross- Desensitization with TRPV1. The target cell for TRPA1 antagonist activity is the sensory neuron. We will use the short term culture of dispersed DRG neurons to examine drug effects on native TRPA1 channels within sensory neurons in order to confirm physiological relevance. The final Phase 1 milestone is to deliver an advanced lead molecule and backup compounds that have all properties necessary for nomination to a full development program in Phase 2. Phase 2 will consist of progressing compounds meeting criteria into animal efficacy testing in multiple pain models, PK studies in rat using oral dosing, and toxicity testing. PUBLIC HEALTH RELEVANCE: NARRATIVE The overall objective of this research is to identify and develop a novel drug product for the treatment of chronic pain that is a functional antagonist of TRPA1 receptor-channel. Current therapeutics are inadequate in addressing patient needs and present significant safety, efficacy, tolerability and addiction concerns that often limit use. TRPA1-receptor/channels play a highly specific function in sensory nerves that transmit the sensations of pain and hyperalgesia in response to inflammation as well as nerve injury. Since TRPA1 is one of the most important signal integrators for pain in sensory nociceptors, targeting TRPA1 is a logical approach to block nociceptive signals at the first stage of neural processing. A TRPA1 antagonist will function as a peripherally acting analgesic and is thus designed to be without addictive and abuse potential. Algomedix employs an innovative rational pharmacology approach which has proven capable of identification of multiple new chemical scaffolds with potency equivalent to established TRPA1 ligands. Algomedix employs a kinetic selectivity profiling approach to characterize drug action which has resulted in identification of new pharmacologic classes for TRPA1. Our approach can identify TRPA1 ligands which are classical antagonists, desensitizing agonists, inverse agonists and allosteric modulators.